A universal characteristic of aging is the loss of regenerative capacity leading to an impaired ability to respond to stress and therefore increased morbidity and mortality. This loss of regenerative capacity suggests that aging is associated with or is caused, in part, by the loss of functional stem cells necessary for tissue regeneration.
Mice greater than two years of age are known to have a significant reduction in the number and proliferative capacity of neural stem cells and male germ-line stem cells. In contrast hematopoietic stem cell (HSC) numbers are preserved as mice age, but the function of the cells is impaired. Muscle satellite cells also lose stem cell properties with aging, but how many satellite cells are present as the animal ages remains controversial. Aging-related changes in bone marrow-derived mesenchymal stem cells (MSCs) include loss of proliferation and differentiation potentials; increase in senescence; and loss of capacity to form bone in vivo. MSCs derived from the bone marrow of patients with Hutchinson-Gilford progeria syndrome, a disease of dramatically accelerated aging, are defective in their ability to differentiate. Adipose-derived multipotent cells display an age-dependent loss of self-renewal capacity and an increased propensity for adipogenesis.
Despite the observed correlation of decline in stem cell population with aging, it is unclear whether the decline of number of stem cells or the dysfunction of remaining stem cells results in aging-related degenerative changes.
Numerous studies provide evidence that the number and/or function of diverse adult stem/progenitor cell populations decline with aging. However, these are largely correlative studies that do not discriminate if changes in the stem cell compartment play a causative role in aging or are merely a consequence of aging. Moreover, prior studies fail to disprove that loss of stem cell population is not merely a biomarker of aging.
Genetic studies revealed proteins and pathways essential for the maintenance of stem cell function. Mutation of these genes leads to foreshortened lifespan and early onset of some aging-related pathologies. For example, mice deficient in the polycomb protein BMI-1 have a short lifespan along with defects in self-renewal of HSCs leading to adult stem cell depletion. Similarly, mice deficient in HMGA2 display reduced stem cell numbers and function (self-renewal) throughout the central and peripheral nervous systems. Finally, HSC function and regenerative capacity are significantly diminished in mice harboring mutations in diverse DNA repair genes or telomerase (Lig4Y288C, Ku80−/−, XpdTTD, and mTR−/−) indicating that genome and telomere maintenance are crucial for stem cell function. However, there is no evidence that loss of stem cell function is directly responsible for decreased lifespan and aging-related pathology in these models.
Thus, there is a need in the art for additional means for extending lifespan and/or improving health in an aging or aged mammal.